Hydroxy diphenyl sulphide derivatives



Patented Dec. 29, 1936 UNITED STATES HYDROXY DIPHENYL SULPHIDE DERIVATIVES Treat B. Johnson, Bethany, C'onn., assignor to Sharp & Dohme, Incorporated, Philadelphia, I Pa., a corporation of Maryland No Drawing. Application June 29, 1935, Serial No. 29,099

12 Claims.

This invention relates to new derivatives of phenolic and ethereal diaryl sulphides, and includes processes for their preparation. It relates more particularly to derivatives of diaryl sul- 5 phides which have, in one position para to the sulphur linkage, a phenolic or ethereal substituent, and in the other para position a halogen.

This application is a continuation in part of my prior application Serial No. 468,468, filed July 16,

1330, now Patent No. 2,017,208, dated Oct. 15,

The phenolic and ethereal compounds prepared according to the present invention have valuable pharmacological and therapeutic properties,

and are useful for certain medicinal purposes. They are also valuable as intermediates for the production of other phenolic and ethereal diaryl sulphide derivatives.

The compounds included within the present invention may be represented by the formula ROR1-S-R2X, in which R represents hydrogen or a hydrocarbon radical, R1 and R2 represent aryl groups, which may be the same or different, and X represents halogen. It is to be understood that the RO group and the halogen are in positions para to the sulfur linkages. Not only are diphenyl sulphide derivatives included within the scope of the invention, but also tolyl phenyl sulphide derivatives, xylyl phenyl sulphide derivatives, and other diaryl sulphide derivatives.

These halogen derivatives are useful not only because of their pharmacological and therapeutic properties, but also as intermediates for the production of other useful phenolic and ethereal compounds. For example, various alcohol, ke-

tone, aldehyde and other aliphatic derivatives may be readily produced by reacting the halides with magnesium to produce reactive compounds of the Grignard reagent type. The halides also serve as intermediates in the production of cyanates, ureides, urethanes, and corresponding thiocompounds.

An advantageous method of producing the phenolic and ethereal derivatives is as follows:

5 An ethereal derivative of a thiophenate is coupled with a halide of a nitrobenzene to produce an alcoxy-nitro-diaryl sulphide, and this is reduced to the corresponding amine. The amine is then diazotized, and the diazonium group replaced 0 by a halogen, to give the etheheal halogen diaryl sulphide. This ether may then be dealkylated to give the phenolic derivative, preferably by the method described in my Patent No. 1,976,732, granted October 16, 1934.

The following examples illustrate the use of this method for the production of 4-methoxy-4'- iodo-diphenyl sulphide and4-hydroxy-4'-diphenyl sulphide, but it is to be understood that these are given by way of illustration, and that other similar compounds can be similarly produced. "5'

Example I .-4-methoxy-4-iodo-diphenyl sulphide 35 parts of para-methoxy-thiophenol are dissolved in 200 parts 95% alcohol and 5.75 parts of metallic sodium are added. This solution of paramethoxy-thiophenate is added to a solution of 40 parts of para-nitrochlorbenzene in 400 parts of 95% alcohol. The mixture assumes adeep red color but after boiling a few minutes this changes to a light orange color and a deposit of salt is formed. The mixture is heated for 4 hours at its boiling point to insure completeness of, the reaction. On cooling, a mass of bright yellow crystals 20 separate. The mixture is filtered'by suction and an additional quantity of the sulphide is obtained by cautiously diluting the filtrate with water. The product, after thoroughly washing with water to remove adhering salt, has been obtained prac- 25 tically pure in yields of 92% or more of theoretical. The -methoxy-l-nitro-diphenyl sulphide crystallizes from alcohol as bright yellow prisms which melt at 71 C.

62 parts of this nitrosulphide are dissolved in 30 600 parts of alcohol and reduced with parts of stannous chloride and parts of hydrochloric acid. The mixture is heated at its boiling point under a reflux condenser for two hours after which the alcohol and most of the hydrochloric acid are 3 removed by distillation under diminishing pressure. From this point two: procedures may be used to isolate the reduction product:

(a) The residue from the distillation is dissolved in water and concentrated ammonium hydroxide is added until precipitation is complete. The mixture of tin hydroxides and free amine is filtered as dry as possible by suction, and the amine extracted with several portions 45 of boiling alcohol. The alcohol extracts are com bined, filtered, and decolorized with charcoal such as norite. On cooling, the free amine separates in glistening, colorless needles, melting at 96. By diluting the alcohol solution with water, 50 all the dissolved amine is separated.

'(b) Hydrochloric acid is added to the residue from the distillation of the alcohol until the stannic chloride addition product of the amine hydrchloride separates completely. After filter- 55 'ing 11 parts of sodiumnitrite.

ing this as dry as possible by suction it is placed in a large separatory funnel, a quantity of crushed ice is added and the mixture covered with a large volume of ether. Concentrated sodium hydroxide (20% solution) is i then added slowly and with shaking until all the solid is dissolved. The clear solution is extracted twice with ether. The extracts combined, dried over sodium sulphate, and the amine precipitated as its hydrochloride by adding an alcoholic solution of hydrogen chloride. A white flocculent precipitate is obtained which crystallizes from hydrochloric acid solution in silkyneedles, melting with decomposition at 205-207.*

40 parts of the hydrochloride of the'amine prepared by either method are dissolved in a mixture of 25 parts of concentrated hydrochloric acid and 500 parts of water by heating. The hydrochloride is obtained in a state of fine division by rapidly cooling and stirring the solution. The thick suspension of fine white needles is cooled to 0 C. and diazotized with a solution contain- The crystals of the hydrochloride dissolve as the diazotization proceeds, and a greenish brown solution of the diazonium salt is obtained. This is dropped rapidly into a concentrated solution of potassium iodide containing 50 parts of the salt in 100 parts of water. An orange red suspension is formed which changes to a black spongy mass when warmed. When the nitrogen is completely evolved this settles as a dark brown oil. The

.free iodine formed in the reaction is removed Example II.4-hydro:cy-4-iodo-diphenyl sulfide 43 parts of the methoxy derivative of Example Iare dissolved in a mixture of 85 parts of 48% hydrobromic acid solution and 246.5 parts of acetic acid. After heating the solution in an oil bath under a reflux condenser at 80-85 for ten hours, thehydrobromic acid and most of the acetic acid are removed by distillation under diminished pressure. An excess of 5% sodium hydroxide solution is added to the residue and the mixture heated on the steam'bath for an hour to insure hydrolysis of any acetylated phenol that may be formed. After cooling, the mixture is extracted with ether. The extracts are combined and dried over anhydrous sodium sulphate. After removal of the ether, 13.7 parts of unch'anged'methoxy derivatives are recovered. The alkaline solution is acidified with d1- lute sulphuric acid and extracted with ether.

7 The extracts are dried and the ether removed.

hydroxide solution from which it may be repreone part in sixty thousand, but in 20% alcohol it is retained in a dilution of one part in eight thousand.

The chlorine and bromine phenols and ethers maybe prepared in a similar manner, except that the intermediate diazonium compound is dropped into a warm concentrated solution of' 'cuprous chloride or bromide, or into a solution of hydrochloric or hydrobromic acid in the presence of copper dust.

In this application I claim only those diaryl sulphide derivatives in which one para hydrogen In 5%. alcohol it crystallizes from dilutions as high as is replaced by an alkoxy or hydroxy group, and a the other para hydrogens by a halogen. The intermediate nitro and amino compounds and methods of preparing them are claimed in my application Serial No. 29,100 filed of even date in which are also claimed other phenolic or ethereal diary] sulphides which have. as a para substituent a nitrogen-containing group.

I claim:

1. Compounds of the group consisting of 4- alkoxy-i'halo-diphenyl sulfides and 4-hydroxy- 4'-halo-diphenyl sulfides.

2. Compounds of the formula where R is hydrogen or alkyl, and X is halogen.

3. 4-alkoxy-4'-halo-dlpheny1 sulfides.

. 4-hydroxy-4'-halo-diphenyl sulfides.

. 4-methoxy-4-iodo-diphenyl sulfides.

. 4-hydroxy-4'-iodo-diphenyl sulfides.

. 4-methoxy-4'-iodo-diphenyl sulfide.

. 4-hydroxy4'-iodo-diphenyl sulfide.

.The method of preparing compounds of the group consisting of p-alkoxy and p-hydroxy p'-halogen' diphenyl sulfides which comprises coupling a para alkyl ether of a thiophenate with para nitro-chlorbenzene, reducing to the amine,

diazotizing', and converting the diazonium compound to the halide, with elimination of the diazonium group.

p 10. The method of producing 4-alkoxy-4'- iodo-diphenyl sulfide which comprises coupling a para alkyl ether of a thiophenate with para nitrochlorbenzene, reducing to the amine, di-

azotizing, and converting the diazonium compound to the iodide by reaction with potassium iodide.

11. The method of producing 4-methoxy-4- iodo-diphenyl sulfide which comprises coupling a para methyl ether of a thiophenate with para nitrochlorbenzene, reducing to the amine, diazotizing, and converting the diazonium compound to the iodide by reaction with potassium iodide.

12. The method of producing 4'-hydroxy-4'- iodo-diphenyl sulfide which comprises coupling a para alkyl ether of a thiophenate with para nitrochlorbenzene, reducing to the amine, diazotizing, converting the diazonium compound to the iodide by reaction with potassium iodide, and dealkylating.

.TREAT B. JOHNSON. 

